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AAPS 2007 Annual Meeting, May 19 - 22, 2007, The Coeur d'Alene Resort, Coeur d'Alene, Idaho.
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Activation of the Tumor Suppressor Gene p53 is Higher in Normal Parous Human Breast Tissue than the Nulliparous Counterpart
Kristin Stueber, M.D.1, Lesley Matthews2, Brooke Pazik2, Giovanna Crisi, MD3, D. Joseph Jerry, PhD2, Sallie Smith-Schneider, PhD2.
1Baystate Medical Center, Springfield, MA, USA, 2Pioner Valley Life Sciences Center, Springfield, MA, USA, 3Baystate Medical Center, Pathology, Springfield, MA, USA.

Purpose: Breast cancer is the most frequently diagnosed cancer in women in the United States. A full term pregnancy at an early age, especially when younger than age 24, is associated with a significant reduction in the risk of developing breast cancer. Identifying the molecular basis of the protective effect of parity will provide novel targets for prevention and treatment of breast cancer.
The role of p53 in mediating hormone-induced resistance to mammary cancer has been well-documented in mouse models. The importance of p53 in mediating estrogen and progesterone mediated protection is highlighted by the inability of parity or ovarian hormones to induce a significant protection in p53-null mammary epithelium. Therefore, we hypothesized that tissue cultured from women experiencing an early full term pregnancy would have increased levels of radiation-induced p53 activity as compared to nulliparous tissue, or tissue from women experiencing a later full term pregnancy.
Materials and Methods: Women undergoing elective breast reduction surgery were asked to voluntarily enroll in an IRB sanctioned study. A pre-operative questionnaire was administered to obtain information about onset of menses, last menses, parity, age at first pregnancy, and family history of breast cancer. On the day of surgery, a portion of the patient’s tissue was harvested for explant cultures.. Two 500 mg portions of tissue were cultured on gelatin sponges for 24 hours in a 37º incubator. Cultures were then exposed to ionizing radiation (5 Gy). Duplicate cultures remained unirradiated to provide a control. The tissue was placed back in the incubatorfor 6 hours, then the tissue was fixed and immunohisotchemical staining was performed for p53. A pathologist examined each sample and epithelial cells were scored on an intensity scale of 0-3. Differences in p53 scores between each patient’s initial tissue and irradiated tissue were calculated and reported.
Results: A total of 42 patients have been enrolled with 11 being nulliparous, 24 experienced a first pregnancy under the age of 25 years, and 7 had a first pregnancy when greater than age of 26 years. A significant increase in percentage of cells staining positive for p53 was observed in patients experiencing a parity before the age of 25 (percent = 50%, compared to nulliparous women (23%, respectively; p-value = 0.004). Patients who had a pregnancy over the age of 25 demonstrated only 37% of their cells staining positive for p53, and although this was lower than those patients experiencing a younger parity, it was not statistically significant.
Conclusion: The study presented here demonstrates an enhancement of the responsiveness of p53 in breast tissues from women who had full term pregnancies at early ages. These are the first results using cultured human mammary tissue to demonstrate results consistent with observations in rodent systems. This demonstrates that, like mice, parity enhances the responsiveness of p53. The results p53 as a mechanism of protection conferred to women who have an early full term pregnancy and could further explain how they are less at risk for the occurrence of breast cancer.
* p-value = 0.004

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